IMPORTANCE OF GENETIC COUNSELING AND TESTING IN MALE BREAST CANCER SURVIVORS
Genetic factors play a role in male breast cancer. BRCA mutations, in particular BRCA2 mutations, are significantly associated with male breast cancer. Most population-based studies show that 10%–15% of men with breast cancer carry a mutation in BRCA2. Furthermore, approximately 5%–10% of men with BRCA2 mutations will develop breast cancer at some point in their lives.4,37 The frequency of these mutations differs drastically among different ethnicities and countries, as some populations carry founder mutations. In Iceland, for instance, the BRCA2 999del5 founder mutation is seen in over 40% of male breast cancer cases.38 The median age of diagnosis in BRCA2 mutation carriers is 58.8 years, almost a decade younger than that in nonmutation carriers.37 There is some evidence that men with BRCA2 mutations who develop breast cancer tend to have more aggressive disease as well.6,37 BRCA1 is less closely linked to male breast cancer (multiple series have shown that <5% of men with breast cancer carry a BRCA1 mutation).4,7,37,39,40 Some male BRCA carriers with a history of breast cancer opt for bilateral mastectomies to reduce risk of future breast cancers, but the incidence of ipsilateral and contralateral new primaries remains poorly studied in male survivors with deleterious BRCA mutations.
Mitri et al recently published results that validate the use of BRCAPRO testing in men.44 BRCAPRO, which has been validated in other populations, is a model that uses personal cancer history, family cancer history, age at cancer diagnosis, risk-reducing surgery history, ethnicity, and current age or age at death of included individuals to determine risk of carrying a BRCA mutation.41–44 This study assessed 148 men, one-third of whom had been diagnosed with breast cancer. Other diagnoses included pancreatic cancer, prostate cancer, and other primary cancers. There were 37 men in the study who did not have a personal history of cancer. Fifty patients (34%) tested positive for a BRCA mutation (22 BRCA1, 27 BRCA2, and 1 with both BRCA1 and BRCA2). The authors found that the median BRCAPRO score was significantly higher for those who tested positive and that the test had appropriate sensitivity, specificity, positive predictive value, and negative predictive value for validation in this population.44
Mutations in other genes including CHEK2 and CYP17, have also been implicated in male breast cancer. CHEK2 is a cell cycle checkpoint kinase that contributes to DNA repair. The CHEK2 1100delCmutation is estimated to contribute to 9% of male breast cancer cases and increases the risk of breast cancer 10-fold in men without BRCA mutations.8,45 Mutations in CYP17, a gene involved in the synthesis of estrogen from androgen, have been associated with an increased male breast cancer risk in small studies, but more research is needed in this area.9 There has also been at least one case of male breast cancer detected in a carrier of a deleterious mutation in MLH1, a mismatch repair gene.46
Genetic testing recommendations
Owing to the strong link between BRCA2 mutations and male breast cancer, we agree with the NCCN recommendation that all male breast cancer survivors be offered genetic counseling and testing based on their risk of carrying a deleterious mutation that might be relevant to their own care or the care of their family members.47
MANAGING LONG-TERM TREATMENT SEQUELAE
Adherence to endocrine therapy
Men with breast cancer deal with substantial physical, emotional, and social sequelae of this disease. Although the majority of male patients are treated with endocrine therapy because their tumors are usually strongly hormone receptor positive, studies have shown that at least 25% of men discontinue this medication, likely at least in part due to treatment side effects.48–50 Visram et al published a retrospective review of 59 male breast cancer patients of whom 42 (71%) received endocrine therapy. Tamoxifen was used in 38 patients, and their most common side effects were hot flashes, weight gain, decreased libido, fatigue, pulmonary embolism, depression, and rash. Tamoxifen was prematurely discontinued in 24% of men due to these side effects. Aromatase inhibitors (anastrozole and letrozole) were used in 13 of the 42 patients, and 11 of the 13 had previously taken tamoxifen. Commonly reported side effects of the aromatase inhibitors included decreased libido, peripheral edema, depression, and hot flashes.49 Pemmaraju et al published another study evaluating 64 male breast cancer patients on tamoxifen. Thirty-four (53%) experienced significant side effects, the most common of which were weight gain and sexual dysfunction; 20.3% of these men discontinued endocrine therapy prematurely.50
Thus, it seems in small studies that men with breast cancer who are on endocrine therapy suffer from similar side effects as women who receive these treatments, and are therefore as likely to prematurely discontinue treatment, potentially forfeiting a therapeutic benefit. Although the impact of adjuvant endocrine therapy and lifestyle modifications are only well established in female survivors, it is reasonable to regularly assess adherence to endocrine therapy and to encourage a healthy and active lifestyle (including maintenance of normal body mass index) in male breast cancer survivors. Care providers need to be aware of the side effects of treatment in men in order to offer management strategies and encourage adherence in this population.
The use of aromatase inhibitors in the treatment of breast cancer has been linked to bone loss and fractures in women.51–55 As a result, NCCN recommends periodic bone mineral density testing in women on aromatase inhibitor therapy. In contrast, tamoxifen only causes bone thinning in premenopausal women and improves bone density in postmenopausal women. It is unknown how a man’s bone density changes during treatment with tamoxifen or aromatase inhibitors. GnRH-a medications, commonly used in the treatment of prostate cancer, have also been linked to increased bone loss and fractures. Multiple studies have shown annual rates of bone loss of 2%–8% in the lumbar spine and 1.8%–6.5% at the femoral neck in men on GnRH-a therapy,56–62 with the highest rates of bone loss occurring during the first year of treatment.63,64 GnRH-a medications have also been associated with an increased risk of fracture.65–67 Taylor et al performed a systematic review with a total of 100,000 men on androgen-deprivation therapy and reported a relative risk of skeletal fracture associated with GnRH-a of 1.23 (95% CI 1.10–1.38) and a relative risk of vertebral fracture associated with GnRH-a of 1.39 (95% CI 1.20–1.60).68 Therefore, the importance of bone mineral density testing in male survivors remains unclear. Recommendations from the National Osteoporosis Foundation (http://www.nof.org) should be followed in this setting (including use of supplemental calcium 1,200 mg daily and vitamin D3 800–1,000 IU daily for all men over age 50). Calculation of a FRAX score may help determine the need for baseline and follow-up dual energy X-ray absorptiometry during adjuvant endocrine therapy for male breast cancer.69